Monoclonal antibodies (mAbs) have been employed as targeting biomolecules for the delivery of radionuclides into tumor cells in radioimmunotherapy (RIT). Numerous clinical trials have been performed to validate this modality of cancer therapy (see, for example, Parker et al., Pure Appl. Chem., 1991, 63, 427–463; Chakrabarti et al., J. Nuc. Med., 1996, 37, 1384–1388; Sharkey et al., Cancer Res., 1988, 48, 3270–3275; Sharkey et al., Cancer Res., 1988, 48, 3270–3275; and Lee et al., Cancer Res., 1990, 50, 4546–4551). Several useful β−-emitting radionuclides, including 131I, 90Y, 177Lu, and 153Sm, have been employed for labeling mAbs for RIT applications (Denardo et al., Cancer, 1994, 73, 1012–1022; Scott et al., Cancer, 1994, 73, 993–998; Schlom et al., Cancer Res., 1991, 51, 2889–96).
The pure β−-emitting radionuclide 90Y (Emax=2.28 MeV; t1/2=64.1 h) has been extensively studied in RIT due to its physical properties (see, for example, Martell et al., Critical Stability Constants, Vol. 1: Amino Acids. Plenum Press: New York, 1974; pp. 281–284; Wessels et al., Med. Phys., 1984, 11, 638–645; Chinol et al., J. Nucl. Med. 1987, 28, 1465–1470; and Mausner et al., Med. Phys., 1993, 20, 503–509). The macrocyclic chelating agent 1,4,7,10-tetraazacyclododecane-N,N′,N″,N′″-tetraacetic acid (“DOTA”)
is well-known to be an effective chelator of Y(III) and lanthanides. Numerous bifunctional analogs of DOTA suitable for protein conjugation have-been reported in the literature (Szilágyi et al., Inorg. Chim. Acta., 2000, 298, 226–234; Kodama et al., Inorg. Chem., 1991, 30, 1270–1273; Kasprzyk et al., Inorg. Chem., 1982, 21, 3349–3352; Cox et al., J. Chem. Soc. Perkin Trans. 1, 1990, 2567–2576; Kline et al., Bioconjugate Chem., 1991, 2, 26–31; and McCall et al., Bioconjugate Chem., 1991, 1, 222–226). Although the Y(III)-DOTA complex shows ideal stability in vitro and in vivo, the extremely slow formation rate of the complex complicates and limits its routine use in RIT applications.
In general, DOTA conjugated to mAbs displays relatively slow and inefficient radiolabeling with Y(III) isotopes under mild conditions. This is contrary to the rapid and high-yield radiolabeling (>90%) of mAbs conjugated with bifunctional derivatives of the acyclic chelating agent diethylenetriaminepentaacetic acid (DTPA) (Stimmel et al., Bioconjugate Chem., 1995, 6, 219–225; and Harrison et al., Nucl. Med. Biol., 1991, 18, 469–476). Low-yield radiolabeling requires chromatographic purification of the product to separate unchelated Y(III), which is not always practical for RIT applications.
Since the release of the radiometal from the chelate is a potential source of radiotoxic effects to non-tumor cells and normal tissue, a chelate that forms a kinetically inert complex with the radiometal is critical for successful targeted radiotherapy. Complex stability comparable to that of DOTA and complexation kinetics characteristics of DTPA are also desirable. Efforts to achieve a chelate with these characteristics have resulted in the synthesis and evaluation of several chelates including CHX-DTPA:
(Kobayashi et al., J. Nucl. Med., 1997, 38(suppl), 824–824; McMurry et al., J. Med. Chem., 1998, 41, 3546–3549; Camera et al., J. Nuc. Med., 1994, 35, 882–889; Brechbiel et al, J. Chem. Soc. Perkin Trans. 1, 1992, 1173–1178; and Kobayashi et al., J. Nucl. Med., 1998, 39, 829–836) and 1B4M-DTPA:
(Harrison et al., Nucl. Med. Biol. 1991, 18, 469–476; and Brechbiel et al., Bioconjugate Chem. 1991, 2, 187–194), which display significantly improved complexation kinetics with Y(III) as compared to DOTA. However, the corresponding radio-yttrium complexes remain somewhat less stable in vitro and in vivo.
Therefore, there is still a need for a compound that possesses complex stability comparable to that of DOTA, the excellent practical complexation kinetics of DTPA, and increased stability in vitro and in vivo. The invention provides such a compound. This and other objects and advantages, as well as additional inventive features, will be apparent from the description of the invention provided herein.